Modeling Cellular Determinants of Cognitive Decline in Aging

衰老过程中认知能力下降的细胞决定因素建模

• 批准号: 8318136
• 负责人: PATRICK R HOF
• 金额: $ 40.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318136
• 关键词: Action Potentials; Address; Age; Aging; Animals; Architecture; Brain Diseases; Cell model; Cell physiology; Cells; Cereals; Communities; Computer software; Computing Methodologies; Custom; Data; Databases; Dendritic Spines; Dependence; Development; Disease; Electrophysiology (science); Financial compensation; Fluorescence Microscopy; Future; Genetic Programming; Goals; Image; Image Analysis; Impaired cognition; In Vitro; Ion Channel; Location; Macaca mulatta; Measurement; Measures; Membrane; Methods; Modeling; Monkeys; Morphology; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Pathologic; Pattern; Physiology; Prefrontal Cortex; Primates; Property; Pyramidal Cells; Resolution; Resources; Slice; Specific qualifier value; Structure; Synapses; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Vertebral column; age related; aged; base; behavior test; biocytin; cognitive function; design; human disease; innovation; insight; morphometry; multidisciplinary; new technology; normal aging; novel; parallel computing; patch clamp; postsynaptic; response; tool

PROJECT SUMMARY Cognitive decline in normal aging is accompanied by morphologic changes on many scales, and in rhesus monkeys, by single cell electrophysiological changes such as altered firing rates and synaptic responses. A subset of 'successful agers' can maintain both normal cognitive function and normal single-cell electrophysiology, suggesting some form of adaptive compensation for morphologic dystrophy at the cellular level. To date, no mechanistic understanding of these cellular changes, nor the inferred compensatory mechanisms, exists. The goal of this unique multidisciplinary project is to develop innovative computational technologies for identifying causal mechanisms underlying the cognitive decline that accompanies aging and neurodegeneration. Based upon these mechanisms, this project will design quantitatively precise strategies for compensating or reversing these changes, to restore a given cellular-level function to normal levels. Three Specific Aims will address this broad objective: (1) To reconstruct the morphology, including dendritic spines, of electrophysiologically characterized young and aged layer 3 (L3) pyramidal cells from the prefrontal cortex of rhesus monkeys that have underwent behavioral testing; (2) To develop morphologically accurate compartment models of young and aged L3 pyramidal cells while developing novel parameter optimization tools; and (3) To predict compensatory mechanisms for restoring normal function in aged or dystrophic neurons using newly-designed sensitivity-analysis techniques. Public dissemination of the 3D morphology and physiology of young and aged neurons from behaviorally characterized primates will provide a unique database for the general neuroscience community to begin to address important cellular and system-level questions. Dissemination of all modeling and analysis software will provide the computational community with efficient tools to apply and extend these techniques. Such studies will generate crucial insight into the cellular bases of aging- and neurodegenerative disease-related changes in cognitive function. The development of novel technologies to predict mechanisms that can compensate for specific morphologic changes to restore a given cellular level function, has far-reaching implications for designing therapeutic interventions for many human diseases.

项目总结